This invention relates to the use of prostaglandin agonists to lower the intraocular pressure of mammals and thus treat glaucoma in mammals, including humans.
Ocular hypertensive agents are useful in the treatment of a number of various ocular hypertensive Conditions, such as post-surgical and post-laser trabecuclectomy ocular hyper-tensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma; are not yet known. The increased intraocular tension is due to the obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed. and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior Synechia in iris bombe and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central rectinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, topical, xcex2-adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Prostaglandins were earlier regarded as potent ocular hypertensives, however, evidence accumulated in the last two decades shows that some prostaglandins are highly effective ocular hypotensive agents and are ideally suited for the long-term medical management of glaucoma (See, for example, Starr, M. S. Exp. Eye Res. 1971, 11, pp. 170-177; Bito, L. Z. Bilogical Protection with Prostaglandins Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune and Stratton, 1984, pp. 477-505). Such prostaglandins include PGF2xcex1 PGF1xcex1 PGE2 and certain lipid-soluble esters, such as C1 to C5 alkyl esters, e.g. 1-isopropyl ester, of such compounds.
In the U.S. Pat. No. 4,599,353 certain prostaglandins, in particular PGE2 and PGF2xcex1 and the C1 to C5 alkyl esters of the latter compound, were reported to possess ocular hypotensive activity and were recommended for use in glaucoma management.
Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow [Nilsson et al., Invest. Ophthalmol Vis. Sci. 28(suppl), 284 (1987)].
The compounds used in the methods herein were first claimed in PCT application No. PCT/IB 97/01417 filed on Nov. 10, 1997 which claims priority from a U.S. application filed on Dec. 20, 1996.
Although there are a variety of treatments for glaucoma there is a continuing need and a continuing search in this field of art for alternative glaucoma therapies.
This invention is directed to a method for reducing intraocular pressure in a mammal (including humans male or female) comprising administering to a mammal a therapeutically effective amount of a compound of Formula I or Formula IA or a pharmaceutically acceptable salt or prodrug thereof.
In one aspect the Formula I or Formula IA compound is applied locally.
A preferred dosage is about 0.001 to 100 mg/kg/day of the Formula I or Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof. An especially preferred dosage is about 0.01 to 10 mg/kg/day of the Formula I or Formula IA compound or a pharmaceutically acceptable salt or prodrug thereof.
The Formula I compounds are herein described below as those compounds having the following Formula I: 
or a pharmaceutically-acceptable salt or prodrug thereof wherein either (i):
B is N;
A is (C1-C6)alkylsulfonyl, (C3-C7)cycloalkylsulfonyl, (C3-C7)cycloalkyl(C1-C6)alkylsulfonyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C1-C4)alkyl or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C1-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1-C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C1-C8)alkylene, thio(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalky(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy;
or (ii):
B is N;
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1-C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is (C1-C8)alkylene, thio(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are H, hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalky C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy
and with the proviso that 6-[(3-Phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and its ethyl ester are not included
or (iii):
B is C(H);
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C1-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1-C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C1-C8)alkylene, thio(C1-C4)alkylene, (C4-C7)cycloalkyl(C1-C6)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are H, hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted independently on carbon with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy.
A preferred group of compounds, designated the A Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl or (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, said A moieties optionally mono-, di-, or tri-substituted on carbon with fluoro;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is methylene or ethylene;
Ar, Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
R2 and R3 are chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A group of compounds which is preferred among the A Group of compounds designated the B Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2 wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl;
V is a bond or (C1-C2)alkylene;
R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro or fluoro.
Especially preferred compounds within the B Group of compounds are
7-[(2xe2x80x2-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid,
7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoic acid, and
7-[(2xe2x80x2-Chloro-biphenyl4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid.
Especially preferred compounds within the B Group of compounds are compounds wherein
a.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(2-hydroxymethylphenyl)phenyl;
b.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(3-hydroxymethylthien-2-yl)phenyl; and
c.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(2-chlorophenyl)phenyl.
A preferred group of compounds, designated the C Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;
M is xe2x80x94Ar, said xe2x80x94Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl or chromanyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted
independently with hydroxy, fluoro or chloro; and R2 and R3 are each independently hydroxy, halo, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl formyl, difluoromethoxy, trifluoromethoxy or carbamoyl.
It is especially preferred for Group C compounds that K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
A group of compounds which is preferred among the C Group of compounds, designated the D Group, contains those compounds wherein
K is methylene;
A is (C1-C3)alkylsulfonyl;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein xe2x80x94Ar is substituted with at least R1;
R1 is (C1-C7)alkyl or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
Especially preferred among the D Group of compounds are
7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid,
7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid,
7-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoic acid and
(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid.
A group of compounds which is preferred among the D Group of compounds, designated the E Group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-; and
W is oxy.
A group of compounds which is preferred among the D Group of compounds, designated the F Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
Especially preferred compounds among the F Group of compounds are compounds wherein
a.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(1-hydroxy-n-hexylene-1-yl)phenyl;
b.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(n-butylene-1-yl)phenyl; and
c.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 5-(1-hydroxy-n-hexylene-1-yl)thien-2-yl.
A group of compounds which is preferred among the D Group of compounds, designated the G Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the H Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the I Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
An especially preferred compound within the I Group of compounds is a compound wherein
A is methylsulfonyl;
Q is 3-methylenephenylmethyl;
Z is carboxyl;
K is methylene; and
M is 4-(n-butylene-1-yl)phenyl.
A group of compounds which is preferred among the D Group of compounds, designated the J Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the D Group of compounds, designated the K Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the D Group of compounds, designated the L Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the M Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the D Group of compounds, designated the N Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the O Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the D Group of compounds, designated the P Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the D Group of compounds designated the Q Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the C Group of compounds designated the R Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
K is (C1-C8)alkylene;
xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxine, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
Preferred compounds among the R Group are
7-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid,
7-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid and
5-(3-{[-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid.
A group of compounds which is preferred among the R Group of compounds, designated the S Group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-; and
W is oxy.
A group of compounds which is preferred among the R Group of compounds, designated the T Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
Especially preferred compounds among the T Group are compounds wherein
a.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is propylene; and
M is 3-chlorophenyl; and
b.
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is propylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the R Group of compounds, designated the U Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the V Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
An especially preferred compound among the V group is a compound wherein
A is methylsulfonyl;
Qxe2x80x94Z is 3-(2-carboxylthien-5-yl)-n-propylene
K is propylene; and
M is 3-chlorophenyl.
A group of compounds which is preferred among the R Group of compounds, designated the W Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the X Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the R Group of compounds, designated the Y Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the R Group of compounds, designated the Z Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the A1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the R Group of compounds, designated the B1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the C1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the R Group of compounds, designated the D1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the R Group of compounds, designated the E1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the C Group of compounds, designated the F1 Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
K is oxy(C1-C4)alkylene;
xe2x80x94Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
Especially preferred compounds within the F1 Group are
7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid,
5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid and
N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.
A group of compounds which is preferred among the F1 Group of compounds, designated the G1 group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-; and
W is oxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the H1 Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
An especially preferred compound among the HI group of compounds is a compound wherein
A is methylsulfonyl;
Q is n-hexylene;
Z is carboxyl;
K is oxyethylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the F1 Group of compounds, designated the I1 Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the J1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
An especially preferred compound among the J1 group is a compound wherein
A is methylsulfonyl;
Qxe2x80x94Z is 3-(2-carboxylthien-5-yl)-n-propylene;
K is oxyethylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the F1 Group of compounds, designated the K1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the L1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the M1 Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the N1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the O1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the F1 Group of compounds, designated the P1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the Q1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the F1 Group of compounds, designated the R1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the F1 Group of compounds, designated the S1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the C1 Group of compounds, designated the T1 Group, contains those compounds wherein
A is (C1-C3)alkylsulfonyl;
K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated;
xe2x80x94Ar is phenyl, thienyl, thiazolyl, pyridyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
Especially preferred compounds among the T1 Group are
Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-acetic acid,
Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazolyl-5-yl)-hexyl]-methanesulfonamide,
Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid and
Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid.
A group of compounds which is preferred among the T1 Group of compounds, designated the U1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-; and
W is oxy.
An especially preferred compound among the U1 group is a compound wherein
A is methylsulfonyl;
Q is methyloxy-n-butylene;
Z is carboxyl;
K is trans-2-n-propenylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the V1 Group, contains those compounds wherein
Q is xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with from one to four fluorines.
A preferred compound among the V1 group of compound is a compound wherein
A is methylsulfonyl;
Q is n-hexylene;
Z is 5-(1H-tetrazolyl);
K is trans-2-n-propeneylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the W1 Group, contains those compounds wherein
Q is xe2x80x94Xxe2x80x94(C1-C5)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the X1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C5)alkylene-Xxe2x80x94; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A preferred compound among the X1 Group is a compound wherein
A is methylsulfonyl;
Qxe2x80x94Z is 3-(2-carboxylthien-5-yl)-n-propylene;
K is trans-2-n-propeneylene; and
M is 3,5-dichlorophenyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the Y1 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the Z1 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the A2 Group, contains those compounds wherein
Q is xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and
W is oxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the B2 Group, contains those compounds wherein
Q is xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the C2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl or thienyl.
A group of compounds which is preferred among the T1 Group of compounds, designated the D2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the E2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
W is oxy; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A group of compounds which is preferred among the T1 Group of compounds, designated the F2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
A group of compounds which is preferred among the T1 Group of compounds, designated the G2 Group, contains those compounds wherein
Q is xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-; and
X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
A preferred group of compounds, designated the H2 Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro;
Ar is (C5-C7)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl;
Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1 -C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
R2 and R3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl or carbamoyl.
It is especially preferred for the H2 Group that K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
A group of compounds which is preferred among the H2 Group of compounds, designated the I2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
K is methylene or ethylene;
M is xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl;
V is a bond or (C1-C2)alkylene;
R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C6)alkoxy, said (C1-C4)alkyl and (C1-C6)alkoxy optionally mono-, di-or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro or fluoro.
A group of compounds which is preferred among the H2 Group of compounds, designated the J2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo;
K is methylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein xe2x80x94Ar is substituted with at least R1;
R1 is (C1-C7)alkyl or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A group of compounds which is preferred among the H2 Group of compounds, designated the K2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
K is (C1-C8)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the H2 Group of compounds, designated the L2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
K is oxy(C1-C4)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the H2 Group of compounds, designated the M2 Group, contains those compounds wherein
A is (C3-C6)alkanoyl said (C3-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo;
K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A preferred group of compounds, designated the N2 Group, contains those compounds having the Formula I as shown above wherein
B is C(H);
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;
W is oxy, thio or sulfonyl;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro;
Ar is (C5-C7)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl;
Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
R2 and R3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl or carbamoyl.
It is especially preferred for Group N2 that K is not optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro.
A group of compounds which is preferred among the N2 Group of compounds, designated the O2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
K is methylene or ethylene;
M is xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl;
V is a bond or (C1-mC2)alkylene;
R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di-or tri-substituted independently with hydroxy or fluoro;
R2 and R3 are each independently chloro or fluoro.
A group of compounds which is preferred among the N2 Group of compounds, designated the P2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo;
K is methylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein xe2x80x94Ar is substituted with at least R1;
R1 is (C1-C7)alkyl or (C1-C6)alkoxy, said (C1-C7)alkyl or (C1-C6)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A group of compounds which is preferred among the N2 Group of compounds, designated the Q2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo;
K is (C1-C8)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the N2 Group of compounds, designated the R2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl said A optionally mono-, di- or tri-substituted on carbon independently with halo;
K is oxy(C1-C4)alkylene;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
A group of compounds which is preferred among the N2 Group of compounds, designated the S2 Group, contains those compounds wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo;
K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-, or
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-;
M is xe2x80x94Ar and xe2x80x94Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and
R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
An especially preferred compound of the J2 Group of compounds is a compound wherein
A is propanoyl;
Q is n-hexylene;
Z is carboxyl;
K is methylene; and
M is 4-(n-1-hydroxylhexyl)phenyl.
An especially preferred compound among the H1 Group of compounds is a compound wherein
A is methylsulfonyl;
Q is n-hexylene;
Z is 5-(1H-tetrazolyl);
K is oxyethyl; and
M is 3,5-dichlorophenyl.
An especially preferred compound among the Y1 Group of compounds is a compound wherein
A is methylsulfonyl;
Q is 3-methylenephenylmethyl;
Z is carboxyl;
K is trans-2-n-propenylene; and
M is 3,5-dichlorophenyl.
A preferred group of compounds, designated the T2 Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C3) alkylsulfonyl;
Q is
xe2x80x94(C3-C5)alkylene-Oxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C5-C7)alkylene-, said xe2x80x94(C5-C7)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94(C2-C4)alkylene-Xxe2x80x94,
xe2x80x94(CH2)-meta-phenylene-Oxe2x80x94(CH2)xe2x80x94 optionally mono- or di-substituted independently with methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro
xe2x80x94(CH2)-meta-phenylene-(CH2)xe2x80x94 optionally mono- or di-substituted independently with methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro;
M is xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2 or xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar;
V is a bond or xe2x80x94CH2xe2x80x94;
Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;
X is thienyl, thiazolyl, or furanyl;
K is methylene;
Ar1 is phenyl, (C5-C7)cycloalkyl , furanyl, thienyl, thiazolyl, or pyridyl;
Ar2 is (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl, triazolyl or pyrazolyl;
R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and
R2 and R3 are each independently, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
A group of compounds which is preferred among the T2 group of compounds, designated the U2 Group, contains those compounds wherein
Q is
xe2x80x94(CH2)-meta-phenylene-(CH2)xe2x80x94,
M is xe2x80x94Ar1xe2x80x94Ar2,
Ar1 is phenyl;
Ar2 is (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl, said Ar2 optionally mono- or di-substituted independently with R1 or R2;
R1 is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy; and
R2 is methoxy, chloro or fluoro.
A group of compounds which is preferred among the T2 group of compounds, designated the V2 Group, contains those compounds wherein
Q is
xe2x80x94(CH2)-meta-phenylene-Oxe2x80x94(CH2)xe2x80x94,
M is xe2x80x94Ar1xe2x80x94Ar,
Ar1 is phenyl;
Ar2 is (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl, said Ar optionally mono- or di-substituted independently with R1 or R2;
R1 is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy; and
R2 is methoxy, chloro or fluoro.
An especially preferred compound of the U2 Group of compounds is a compound wherein
A is methylsulfonyl;
Z is carboxyl; and
M is 4-(cyclohexyl)phenyl.
An especially preferred compound of the U2 Group of compounds is a compound wherein
A is methylsulfonyl;
Z is carboxyl; and
M is 4-(thiazol-2-yl)phenyl.
An especially preferred compound of the U2 Group of compounds is a compound wherein
A is methylsulfonyl;
Z is carboxyl; and
M is 4-(pyrazin-2-yl)phenyl.
Especially preferred compounds among the U2 Group are
a. (3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid;
b. (3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid; or
c. (3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid.
A preferred group of compounds, designated the W2 Group, contains those compounds having the Formula I as shown above wherein
B is N;
A is (C1-C3)alkylsulfonyl;
Q is xe2x80x94(C2-C4)alkylene-Xxe2x80x94;
X is thiazolyl or furanyl; said thiazolyl or furanyl optionally mono- or di-substituted independently with methyl, methoxy, fluoro, chloro, trifluoromethyl, difluoromethoxy or trifluoromethoxy;
K is oxy-ethylene or propylene, said propylene optionally being mono-unsaturated;
M is xe2x80x94Ar, said xe2x80x94Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, pyrimidyl, imidazolyl, cyclohexyl, cyclopentyl, cyclobutyl, or cycloheptyl;
R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and
R2 and R3 are each independently methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
A group of compounds which is preferred among the W2 group of compounds, designated the X2 Group, contains those compounds wherein
A is methylsulfonyl;
Z is carboxyl, or (C1-C4)alkoxycarbonyl;
Q is -propylene-Xxe2x80x94;
X is thiazolyl;
K is oxy-ethylene or propylene;
M is phenyl optionally mono- or di-substituted independently with fluoro, chloro, methoxy, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
An especially preferred compound of the X2 Group of compounds is a compound wherein
Z is carboxyl;
K is propylene; and
M is 3-(chloro)phenyl.
An especially preferred compound of the X2 Group of compounds is a compound wherein
Z is carboxyl;
K is oxy-ethylene; and
M is 3,5-dichlorophenyl.
Especially preferred compounds among the X2 Group are
a. 2-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole4-carboxylic acid; or
b. 2-(3-([3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino)-propyl)-thiazole-4-carboxylic acid.
The compounds of Formula IA are herein described below as compounds of Formula IA: 
or a pharmaceutically acceptable salt or prodrugs thereof wherein either (i):
B is N;
A is (C1-C6)alkylsulfonyl, (C3-C7)cycloalkylsulfonyl, (C3-C7)cycloalkyl(C1-C6)alkylsulfonyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy, (C1-C4)alkyl or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C3-C8)alkylene-, said xe2x80x94(C3-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C1-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(C0-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1-C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1xe2x80x94C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C1-C8)alkylene, thio(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94(C1-C3)xe2x80x94Ar2xe2x80x94, xe2x80x94Ar1xe2x80x94(C1-C3)xe2x80x94Sxe2x80x94Ar2xe2x80x94 or xe2x80x94Ar1xe2x80x94(C1-C3)xe2x80x94Sxe2x80x94(C1-C3)xe2x80x94Ar2, wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon, nitrogen or sulfur with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are oxo, hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono-unsaturated and optionally mono- or di-substituted independently with hydroxy or fluoro,
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy;
or (ii):
B is N;
A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo;
Q is
xe2x80x94(C2-C6)alkylene-Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C4-C8)alkylene-, said xe2x80x94(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94Xxe2x80x94(C2-C5)alkylene-,
xe2x80x94(C1-C5)alkylene-Xxe2x80x94,
xe2x80x94(C1-C3)alkylene-Xxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C4)alkylene-Wxe2x80x94Xxe2x80x94(C0-C3)alkylene-,
xe2x80x94(C0-C4)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C2-C5)alkylene-Wxe2x80x94Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other,
xe2x80x94(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94(CO-C5)alkylene-,
xe2x80x94(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-Xxe2x80x94Wxe2x80x94(C1-C3)alkylene-,
xe2x80x94(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, or
xe2x80x94(C1xe2x80x94C4)alkylene-ethynylene-Xxe2x80x94(C0-C3)alkylene-;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-Nxe2x80x94(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, Nxe2x80x94(C1-C4)alkylenesulfonylamino, carboxamido, Nxe2x80x94(C1-C4)alkylenecarboxamido, carboxamidooxy, Nxe2x80x94(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-Nxe2x80x94(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is (C1-C8)alkylene, thio(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro;
M is xe2x80x94Ar, xe2x80x94Ar1xe2x80x94Vxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2, xe2x80x94Ar1xe2x80x94Sxe2x80x94(C1-C3)xe2x80x94Ar2xe2x80x94, xe2x80x94Ar1xe2x80x94(C1-C3)xe2x80x94Sxe2x80x94Ar2xe2x80x94 or xe2x80x94Ar1xe2x80x94(C1-C3)xe2x80x94Sxe2x80x94(C1-C3)xe2x80x94Ar2 wherein Ar, Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said Ar, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon, nitrogen or sulfur with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are oxo, H, hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylamino, carbamoyl, mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-C4)alkylaminosulfinyl;
R1, R2 and R3 are optionally mono-, di- or tri-substituted independently on carbon with halo or hydroxy; and
V is a bond or (C1-C3)alkylene optionally mono-unsaturated and optionally mono- or di-substituted independently with hydroxy or fluoro
with the proviso that when K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy
and with the proviso that 6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and its ethyl ester are not included.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the Formula I compounds include but are not limited to substituents wherein the Z moiety is independently carboxyl and the free hydrogen is replaced by (C1-C4)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton4-yl, di-N,Nxe2x80x94(C1-C2)alkylamino(C2-C3)alkyl (such as b-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,Nxe2x80x94di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
Examplary five to six membered aromatic rings optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur (i.e., X rings) isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered rings optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen (i.e., Ar, Ar1 and Ar2) are cyclopentyl, cyclohexyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-cyclopentyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrroyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatrizaolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.
Further exemplary six member rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-trizainyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl. Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.
Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyi, benzthiazolyl, purinyl, 4Hquinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3, 1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
By alkylene is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene).
By halo is meant chloro, bromo, iodo, or fluoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy .
As used herein the term mono-Nxe2x80x94 or di-N,Nxe2x80x94(C1-Cx)alkyl . . . refers to the (C1-Cx)alkyl moiety taken independently when it is dixe2x80x94N,Nxe2x80x94(C1-Cx)alkyl . . . (x refers to integers).
Unless otherwise stated the xe2x80x9cMxe2x80x9d moieties defined above are optionally substituted (e.g., the mere listing of a substituent such as R1 in a subgenus or dependent claim does not mean that M is always substituted with the R1 moiety unless it is stated that the M moiety is substituted with R1).
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate, through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term xe2x80x9cpyridylxe2x80x9d means 2-, 3-, or 4-pyridyl, the term xe2x80x9cthienylxe2x80x9d means 2-, or 3-thienyl, and so forth.
The expression xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions xe2x80x9creaction-inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The parenthetical negative or positive sign used herein in the nomenclature denotes the direction plane polarized light is rotated by the particular stereoisomer.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates of the compounds of this invention are also included.
The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituents listed in this invention define compounds which will be less stable under physiological conditions (e.g., those containing acetal or aminal linkages). Accordingly, such compounds are less preferred.
DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediamine tetraacetic acid.
Other features and advantages will be apparent from the specification and claims which describe the invention.
In the DETAILED DESCRIPTION OF THE INVENTION reference to xe2x80x9cFormula Ixe2x80x9d is to be interpreted as reference to xe2x80x9cFormula I or Formula IAxe2x80x9d .
In general the compounds of this invention can be made by processes which include processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes may be described in the experimental section.
Some substituents (e.g., carboxyl) may best be prepared through conversion of another functional group (for carboxyl examples are hydroxyl or carboxaldehyde) at a point later in the synthetic sequence.
In general, the Formula I compounds wherein B is nitrogen can be prepared by sequential alkylation of sulfonamide or amide with two appropriate alkyl halides or alkylsulfonates; or reductive amination of an amine containing the necessary acidic functionality (suitably protected) with an aldehyde followed by reaction with an acylating agent or a sulfonyl chloride followed by hydrolysis.
Generally, the compounds of Formula I (wherein B is N (nitrogen) and A, K, M and Q are as described in the Summary) can be prepared according to the methods described in SCHEMES 1 and 2 below. In general, the sequences involve sequential alkylation of the appropriate formula 1 sulfonamide or amide with two appropriate alkyl halides or alkylsulfonates. It is noted that SCHEMES 1 and 2 merely differ in the order of addition of the two alkylating agents. The alkylation order is typically chosen depending on the reactivity of the electrophilic side-chain. In order to reduce the amount of dialkylation which occurs in the first alkylation step, the less reactive electrophilic side-chain is typically introduced first. One of the alkylating agents typically contains a carboxylic acid or acid isostere suitably masked with an appropriate protecting group. In SCHEMES 1 and 2, the formula 3 acid precursor is a carboxylic ester where R represents either a straight chain lower alkyl, preferably methyl or ethyl, or a tert-butyl or phenyl group. Other acid isosteres can be employed by appropriately modifying these SCHEMES using methods known to those skilled in the art (see SCHEME 6 which describes a tetrazol preparation for an example). Typical alkylating agents are primary, secondary, benzylic or allylic and are preferably alkyl bromides or alkyl iodides.
The formula 1 sulfonamide or amide is converted to its anion with a strong base such as sodium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, etc. in an aprotic solvent such as dimethylformamide, tetrahydrofuran (THF) or dimethylformamide/benzene at a temperature of about xe2x88x9278xc2x0 C. to about 100xc2x0 C. The resulting anion is alkylated with the appropriate formula 2 or 3 alkyl halide or alkyl sulfonate (wherein Xxe2x80x2 is the halide or sulfonate) at a temperature of about 0xc2x0 C. to about 100xc2x0 C. to yield the corresponding alkylated formula 4 or 5 compound. In some cases, varying amounts of a side-product resulting from dialkylation of the amide or sulfonamide are obtained and can be removed using chromatographic techniques, preferably by flash chromatography (W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 43, 2923, 1978). The formula 4 or 5 compounds are converted to the anion again using a suitable base such as sodium hydride, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, or potassium carbonate in an aprotic solvent such as dimethylformamide, THF, dimethylformamide/benzene, or acetone at a temperature of about xe2x88x9278xc2x0 C. to about 100xc2x0 C. Alkylation (as described above) with the appropriate second alkyl halide or alkyl sulfonate (formula 3 or 2 compound) provides the corresponding formula 6 ester. The formula 6 ester is hydrolyzed to the corresponding Formula I acid (in cases where R represents methyl or ethyl) with a dilute aqueous basic solution (preferably sodium or potassium hydroxide in aqueous methanol or ethanol), lithium hydroxide in aqueous alcoholic solvent, aqueous tetrahydrofuran at a temperature of about 0xc2x0 C. to about 80xc2x0 C., or by using methods described in xe2x80x9cProtecting Groups in Organic Synthesis,xe2x80x9d Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc., 1991. 
Formula I compounds (e.g., formula 13 or 14 compounds wherein B is N and A, K, M, Q and Z are as defined in the Summary) can also be prepared from amines (see SCHEMES 3-4 for examples). Generally, the appropriate amine starting materials (formula 9 and 10 compounds) can be commercially obtained or can be prepared using methods known to those skilled in the art (see xe2x80x9cThe Chemistry of Amino, Nitroso and Nitro Compounds and their Derivatives,xe2x80x9d Ed. S. Patai, J. Wiley, New York, 1982). For example, according to SCHEMES 3 and 4, the amine starting materials may be prepared from the corresponding formula 7 or 8 nitrlites. Nitriles are either available from commercial sources or can be prepared using methods known to those skilled in the art (see Rappaport, xe2x80x9cThe Chemistry of the Cyano Group,xe2x80x9d Interscience, New York, 1970 or Patai and Rappaport, xe2x80x9cThe Chemistry of Functional Groups,xe2x80x9d pt. 2, Wiley, New York, 1983). The formula 7 or 8 nitrile is reduced with a reducing agent such as borane-tetrahydrofuran complex, borane-methyl sulfide complex, lithium aluminum hydride, or hydrogenation in the presence of Raney nickel or a platinum or palladium catalyst in a protic solvent such as methanol or ethanol at a temperature of about 0xc2x0 C. to about 50xc2x0 C. The resulting formula 9 or 10 amine is converted to either the formula 11 or 12 sulfonamide or amide by treatment (acylation) with an acid chloride or sulfonyl chloride in the presence of a weak base such as triethylamine, pyridine, or 4-methylmorpholine in an aprotic solvent such as methylene chloride or diethyl ether at a temperature of about xe2x88x9220xc2x0 C. to about 50xc2x0 C. Alternatively, coupling of amines of formulas 9 or 10 with carboxylic acids are conveniently carried out in an inert solvent such as dichloromethane or N,N-dimethylformamide (DMF) by a coupling reagent such as 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) in the presence of 1-hydroxybenzotriazole hydrate (HOBT) to generate compounds of formula 11 or 12. In the case where the amine is present as the hydrochloride salt, it is preferable to add one equivalent of a suitable base such as triethylamine to the reaction mixture. Alternatively, the coupling can be effected with a coupling reagent such as benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) in an inert solvent such as methanol. Such coupling reactions are generally conducted at temperatures of about xe2x88x9230xc2x0 C. to about 80xc2x0 C., preferably 0xc2x0 C. to about 25xc2x0 C. For a discussion of other conditions used for coupling peptides see Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., George Theime Verlag, 1974, Stuttgart. Alkylation and if desired, deprotection, of the formula 11 or 12 compound as described in SCHEMES 1 and 2 affords the corresponding acid formula 13 and 14 compound.
The formula 9 and 10 amines may also be prepared via reduction of formula 15 and 16 amides. The reduction can be achieved using reagents such as a borane-tetrahydrofuran complex, a borane-methyl sulfide complex, or diisobutyaluminum hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether at a temperature of about xe2x88x9278xc2x0 C. to about 60xc2x0 C.
The formula 9 and 10 amines can also be obtained from the corresponding nitro precursors by reduction of the nitro group using reducing reagents such as zinc/HCl, hydrogenation in the presence of Raney nickel, palladium, or platinum catalysts, and other reagents as described by P. N. Rylander in xe2x80x9cHydrogenation Methods,xe2x80x9d Academic Press, New York, 1985. 
The description of, and preparation of other amines and alkylating agents useful for the above syntheses are described below in the section entitled PREPARATIONS.
An alternative to the alkylation chemistry described above for the preparation of Formula I compounds (wherein B is N and A, K, M and Q are as described in the Summary) involves reductive amination of an amine containing the necessary acidic functionality (suitably protected) with an aldehyde and is shown in SCHEME 5. Alternatively, the aldehyde may contain the acidic functionality for coupling with an amine.
The reductive amination is typically carried out with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride preferably at a pH of between 6 and 8. The reaction is normally performed in a protic solvent such as methanol or ethanol at temperatures of about xe2x88x9278xc2x0 C. to about 40xc2x0 C. (for a leading reference see A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron Lett. 39, 31, 5595-5598, 1990). Other conditions involve the use of titanium isopropoxide and sodium cyanoborohydride (R. J. Mattson et al, J. Org. Chem. 1990, 55, 2552-4) or preformation of the imine under dehydrating conditions followed by reduction. The resulting formula 42, 42A amine, is transformed to the desired sulfonamide or amide by coupling with an acid chloride, sulfonyl chloride, or carboxylic acid as described in SCHEMES 3 and 4. If desired, hydrolysis provides the corresponding acid. 
The description of and use of aldehydes useful in the above SCHEME 5 may be found in the PREPARATIONS section.
Alternatively, another method of preparing certain Formula I compounds (i.e., formula 60 tetrazoles wherein B is N and A, K, M, and Q are as described above) is described in SCHEME 6. The starting formula 4 sulfonamide or amide is alkylated with the appropriate alkyl halide or sulfonate (wherein Xxe2x80x2 is halide or sulfonate), preferable a primary, secondary, benzylic, or allylic alkyl bromide, iodide, or sulfonate, which contains a nitrile to provide formula 59 compounds. The alkylation is achieved by treatment of the formula 59 compound with a base such as sodium hydride, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide, or potassium carbonate in an aprotic solvent such as dimethylformamide, dimethylformamide/benzene, or acetone. Alkylation occurs at a temperature of about xe2x88x9278xc2x0 C. to about 100xc2x0 C. Preferred conditions for converting the resulting nitrile to the formula 60 tetrazole, involve treatment with dibutyltin oxide and trimethylsilylazide, in toluene at reflux (S. J. Wittenberger and B. G. Donner, J. Org. Chem. 1993, 58, 4139-4141, 1993). For a review of alternative preparations of tetrazoles see R. N. Butler, Tetrazoles, In Comprehensive Heterocyclic Chemistry; Potts, K. T. Ed.; Pergamon Press: Oxford, 1984, Vol. 5, pp 791-838. 
Alternatively, another method of preparing certain Formula I compounds (wherein B is N and A, Q and M are as described in the Summary) is described in SCHEME 7. Formula 46 esters can be prepared using the procedures described earlier (see SCHEMES 1 and 2). Subsequent Heck coupling of this intermediate to an arylhalide (preferably an aryl bromide or aryl iodide), an aryl triflate, or a ring system which contains a vinyl bromide, iodide, or triflate is accomplished with a palladium catalyst, such as palladium acetate or tetrakis(triphenylphosphine)palladium(0) in the presence of a trialkylamine, such as triethylamine. In some cases, a triarylphosphine may be added to the reaction. The reaction is typically performed in an aprotic solvent such as dimethylformamide or acetonitrile at a temperature of about 0xc2x0 C. to about 150xc2x0 C. (see R. F. Heck in Comp. Org. Syn., Vol. 4, Ch. 4.3, p. 833 or Daves and Hallberg, Chem. Rev. 1989, 89, 1433). If desired formula 47 compounds can be hydrolyzed to the corresponding acid. Alternatively, the formula 47 compounds can be hydrogenated and, if desired, further hydrolyzed to the corresponding formula 49 acid. Preferred conditions for hydrogenation involve the use of a palladium or platinum catalyst in an alcoholic solvent such as ethanol or methanol at a temperature of about 0xc2x0 C. to about 50xc2x0 C. In cases where M represents a partially saturated ring system, hydrogenation will generate a saturated ring system. 
Alternatively, another method of preparing certain Formula I compounds (wherein B is N and A, Q, K and M are as described in the Summary and R is as described for SCHEMES 1 and 2) is described in SCHEME 8. Formula 51 compounds can be prepared as described in SCHEMES 1 and 2 by alkylation of formula 5 compounds with an electrophile of formula 2 which contains the appropriate functionality on the ring M, for subsequent conversion to an aldehyde. For example, electrophiles of formula 2 (SCHEME 2) could contain a protected alcohol on the ring, M, which, after alkylation, can be deprotected and oxidized to the aldehyde, using reagents known to those skilled in the art, to generate formula 51 compounds. An alternative method is to alkylate with an electrophile of formula 2 where M contains a vinyl group. After alkylation, oxidative cleavage of the double bond provides the desired formula 51 aldehyde. The oxidative cleavage can be accomplished by transforming the double bond to the 1,2-diol with catalytic osmium tetroxide and N-methylmorpholine followed by oxidative cleavage to the aldehyde using sodium periodate. Alternatively, oxidative cleavage via ozonolysis followed by reduction using reagents such as methyl sulfide, triphenylphosphine, zinc/acetic acid, or thiourea, will generate the desired formula 51 aldehyde. Addition of LMetal where LMetal represents any organometallic reagent such as an organolithium or Grignard reagent in an aprotic solvent such as diethyl ether or tetrahydrofuran at a temperature of about xe2x88x9278xc2x0 C. to about 80xc2x0 C., followed by hydrolysis of the ester as described above, provides the desired formula 50 compound. 
Alternatively, another method of preparing certain Formula I compounds (wherein B is N and A, K, and Q are as described in the Summary) is described in SCHEME 9. The appropriate formula 5 sulfonamide or amide is alkylated using the conditions described in SCHEMES 1 and 2 with an electrophile which contains an aromatic bromide or iodide or a ring system which contains a vinyl bromide or iodide (Art) to provide formula 53 compounds. Suzuki-type coupling of the formula 53 compound with an aryl boronic acid (Ar2) provides formula 53a compounds (for a review of the Suzuki reaction see A. R. Martin and Y. Yang in Acta Chem. Scand. 1993, 47, 221). The coupling reaction is achieved using about two equivalents of a base, such as sodium carbonate, potassium carbonate, sodium hydroxide, thallium hydroxide, potassium phosphate, or sodium methoxide, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), palladium acetate, palladium chloride, tris(dibenzylideneacetone)dipalladium(0) or [1,4-bis(diphenylphosphine)butane]palladium(0). The reaction may be run in aqueous alcoholic solvents (methanol or ethanol), aqueous tetrahydrofuran, aqueous acetone, aqueous glycol dimethyl ether, or aqueous benzene at temperatures ranging from about 0xc2x0 C. to about 120xc2x0 C. When Ar1 represents a partially saturated ring, if appropriate, reduction of the ring to provide a saturated ring system may be performed at this point. Conditions to accomplish this transformation involve hydrogenation in the presence of a catalyst such as palladium or platinum in an alcoholic solvent (ethanol or methanol) and/or ethyl acetate. Ester hydrolysis of formula 53a compounds, if desired, provides the corresponding acid. The resulting acids may contain functional groups on either of the ring systems (Ar1 or Ar2) which can be modified using methods known to those skilled in the art. Examples of such modifications are shown in SCHEME 10. 
Formula 54 compounds which contain an aldehyde functional group can be prepared using methods described in SCHEMES 8 and 9. According to SCHEME 10, treatment of the formula 54 compound with an appropriate organometallic reagent (LMetal), such as an organolithium or Grignard reagent, in an aprotic solvent such as diethyl ether or tetrahydrofuran at a temperature of about xe2x88x9278xc2x0 C. to about 80xc2x0 C., followed by hydrolysis of the ester, provides formula 56 compounds (wherein B is N and A, Q and K are as described in the Summary and Ar1 and Ar2 are as described in SCHEME 9). Alternatively, reduction of the aldehyde followed by hydrolysis provides formula 55 compounds. 
Alternatively, another method of preparing certain Formula I compounds (i.e., formula 57 compounds wherein B is N and A, K, and Q are as described in the Summary and R is as described in SCHEMES 1 and 2 and accordingly the 10 corresponding acids) is described in SCHEME 11. The formula 58 starting alcohol can be prepared using the methods described in SCHEMES 1 and 2. Intermediate 58 is coupled with a variety of aryl alcohols (M represents an aromatic ring) using Mitsonobu conditions (for a review see 0. Mitsonobu, Synthesis, 1, 1981). Typically the coupling is achieved by addition of a coupling agent such as triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate in inert solvents such as methylene chloride or tetrahydrofuran at a temperature of about 0xc2x0 C. to about 80xc2x0 C. If desired, subsequent hydrolysis yields the corresponding acid. 
Alternatively, another method of preparing certain Formula I compounds (i.e., formula 106 compounds wherein B is N and A, K, and M are as described in the 5 Summary and R is as described in SCHEMES 1 and 2 and accordingly, the corresponding acids) is described in SCHEME 12. A formula 102 compound is added to a formula 105 compound (wherein the X is an aromatic ring such as a benzene ring or a thiophene ring) in the presence of a Lewis acid such as titanium tetrachloride or a mineral acid such as hydrochloric acid. If desired the formula 106 ester can be converted to the corresponding acid by hydrolysis or deprotection. 
Alternatively, another method of preparing certain Formula I compounds (i.e., formula 107 or 108 compounds wherein B is N and A, and Q are as described in the Summary and accordingly, the corresponding acids) is described in SCHEME 13. Formula 104 chloromethyl compounds are treated with the appropriate substituted aromatic ring system, M, such as 4-ethoxybenzene or thiophene in the presence of a Lewis acid such as titanium tetrachloride or a mineral acid such as hydrochloric acid in an aprotic solvent such as chloroform at a temperature of about 0xc2x0 C. to about 80xc2x0 C. to yield the formula 107 compound which may subsequently be hydrolyzed or deprotected as described above to yield the corresponding acid. Alternatively, formula 104 chloromethyl compounds can be treated with a Lewis acid such as titanium tetrachloride and an appropriately substituted vinyl silane in an aprotic solvent such as methylene chloride at a temperature of about xe2x88x9250xc2x0 C. to about 50xc2x0 C. to give formula 108 compounds which may subsequently be hydrolyzed or deprotected as described above to yield the corresponding acid. If desired, reduction of the double bond can be accomplished using conditions described in SCHEME 7. 
Alternatively, another method of preparing certain Formula I compounds (i.e., formula 109 compounds, wherein B is N and A, Q, R and M are as described above, and accordingly, the corresponding acids) is described in SCHEME 14. Formula 104 chloromethyl compounds are treated with a Lewis acid such as titanium tetrachloride and an appropriately substituted allyl silane in an aprotic solvent such as chloroform at a temperature of about 0xc2x0 C. to about 80xc2x0 C. to give formula 109 compounds which may subsequently be hydrolyzed or deprotected as described above. 
Alternatively, another method of preparing certain Formula I compounds (i.e., formula 112 compounds, wherein B is N and A, Q, R and M are as described above, and accordingly, the corresponding acids) is described in SCHEME 15. Formula 104 chloromethyl compounds are treated with a formula 111 sulfinic acid in the presence of a base such as triethylamine in an aprotic solvent such as chloroform at a temperature of about xe2x88x9230xc2x0 C. to about 50xc2x0 C. to give formula 112 compounds which may subsequently be hydrolyzed or deprotected as described above to yield the corresponding acid. 
Formula I compounds (wherein B is C(H) and Q, M and K are as described in the Summary, Rxe2x80x2 is a small chain alkyl group, and R1 represents the alkyl groups on A as described in the Summary) can be prepared according to SCHEME 16. Formula 113 beta-ketoesters are alkylated sequentially with formula 114 compounds followed by alkylation of formula 116 compounds to give formula 117 compounds (J. Med. Chem. 26, 1993, p33541). Alkylations can be carried out in a suitable solvent such as DMF, THF, ether, or benzene using an appropriate base such as sodium hydride, LDA, or potassium carbonate at a temperature of about xe2x88x9278xc2x0 C. to about 80xc2x0 C. The resulting formula 117 disubstituted keto esters are hydrolyzed and decarboxylated to give the corresponding formula 118 compound by using an aqueous base such as sodium hydroxide to hydrolyze the ester, followed by an acidic quench such as aqueous hydrochloric acid to effect decarboxylation. 
Alternatively, Formula I compounds (wherein B is C(H) and Q, M and K are as described in the Summary, Rxe2x80x2 is as described above, and RI represents the alkyl groups on A as described in the Summary) may be prepared according to SCHEME 17. Sequential alkylation of a malonate derivative of formula 119 provides the formula 121 dialkylated species. Deprotection of the ester group by treatment with a strong acid such as TFA or HCl in ethanol at a temperature of about xe2x88x9220xc2x0 C. to about 50xc2x0 C. leads to the formula 122 decarboxylated product. Conversion of the acid to an acid chloride using thionyl chloride or oxalyl chloride in an aprotic solvent at a temperature of about xe2x88x9278xc2x0 C. to about 50xc2x0 C. or to a Weinreb amide using methoxymethyl amine in the presence of a suitable coupling agent such as DCC or DEC in an aprotic solvent at a temperature of about xe2x88x9230xc2x0 C. to about 50xc2x0 C. provides formula 123 compounds. Formula 123 are suitable substrates for addition of various organometallic species (e.g., grignard reagents, organo-cadmium reagents) which after hydrolysis of the terminal ester provide the keto-acid compounds of formula 118.
Alternatively formula 118 compounds can be prepared using methods described previously (e.g. see SCHEMES 7, 8, 9, 10, and 11) where one or both of the side chains are further functionalized after attachment. 
Amines, Amides and Sulfonamides
Certain amides or sulfonamides described by formulas 21, 22, and 23 (wherein W and Z are as described in the Summary and X and M are aromatic or saturated ring systems may be prepared according to SCHEME 18. Formula 25, 26 and 27 alkynyl amides or sulfonamides are prepared by coupling a formula 24 alkynyl sulfonamide or amide to an aromatic or vinyl halide, preferably an aromatic or vinyl bromide or iodide (wherein W and Z are as defined above and where X and M represent an aromatic ring or a partially saturated ring system). The coupling is typically accomplished in the presence of copper iodide, a palladium catalyst, such as palladium chloride, bis(triphenylphosphine)palladium dichloride, or tetrakis(triphenylphosphine)palladium(0), and an amine such as triethylamine, diisopropylamine, or butylamine in an aprotic solvent such as acetonitrile at a temperature of about 0xc2x0 C. to about 100xc2x0 C. The resulting formula 25, 26 and 27 alkynes can be converted to the corresponding formula 21, 22 or 23 alkanes, via hydrogenation in the presence of a palladium or platinum catalyst and in solvents such as methanol, ethanol, and/or ethyl acetate at a temperature of about 0xc2x0 C. to about 50xc2x0 C. Alternatively, one can convert the alkyne to the cis-alkene using the Lindlar catalyst (Pd-CaCO3xe2x80x94PbO). In the case where M represents a partially saturated ring system, hydrogenation will convert M to a fully saturated ring system. Alkylation and deprotection as described in SCHEMES 1 and 2 affords the corresponding Formula I compounds. 
According to SCHEME 19 formula 33 compounds (wherein A and X are as described in the Summary) can be prepared from a suitable formula 32 amine (e.g., methoxyarylalkylamine). Formula 32 amines are commercially available or can be prepared by methods known to those skilled in the art (for example, see SCHEME 4) and are converted to formula 31 sulfonamides or amides using methods, for example, described in SCHEME 3 and 4. The resulting formula 31 aromatic methyl ether is deprotected with reagents such as boron tribromide, pyridinium hydrochloride, hydrogen bromide/acetic acid, or other reagents as described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc., 1991. Alkylation with a bromoalkylester using a mild base such as potassium carbonate in an aprotic solvent such as dimethylformamide or acetone at a temperature of about 0xc2x0 C. to about 100xc2x0 C. generates the desired formula 33 amide or sulfonamide. 
Alkylating Agents
Numerous methods exist for the synthesis of the desired alkylating agents used in the above procedures and are known to those skilled in the art (see xe2x80x9cThe Chemistry of the Carbon-Halogen Bond,xe2x80x9d Ed. S. Patai, J. Wiley, New York, 1973 and xe2x80x9cThe Chemistry of Halides, Pseudo-Halides, and Azides,xe2x80x9d Eds. S. Patai and Z. Rappaport, J. Wiley, New York, 1983). Some examples are shown in SCHEMES 20-26. As shown in SCHEME 20, tolyl or allylic substrates can be converted via halogenation to benzylic or allylic bromides (wherein M, X, W and Z are as described in the Summary). This reaction is typically performed with N-bromosuccinimide (NBS) in the presence of a radical initiator such as AIBN or a peroxide, preferably benzoyl peroxide. Alternatively, the reaction can be initiated with light. The reaction is done in an inert solvent such as carbon tetrachloride or chloroform at a temperature of about 50xc2x0 C. to about 100xc2x0 C. 
SCHEME 21 demonstrates the synthesis of alkylating agents useful for preparing Formula I compounds where M represents a biaryl or aryl cyclic group. Suzuki-type coupling of an aryl iodide or bromide or a ring system containing a vinyl bromide or iodide (Ar2) with a methylaryl boronic acid (Art) using the conditions described in SCHEME 9 provides formula 34 compounds. In the case where a vinyl bromide or iodide is used, formula 34 compounds can be reduced to generate a fully saturated ring. The reduction is accomplished by hydrogenation in the presence of palladium or platinum catalysts typically in protic solvents (methanol or ethanol), tetrahydrofuran, or ethyl acetate. Halogenation of the methyl group using reagents and conditions as described in SCHEME 20 provides formula 35 alkylating agents. 
Another common method for accessing alkyl halides is by halogenation of an alcohol or an alcohol derivative. Alcohols are obtained from commercial sources or can be prepared using methods known to those skilled in the art. For example, in SCHEME 22, a carboxylic acid or ester is reduced to the alcohol using reagents such as sodium borohydride, lithium aluminum hydride, borane-tetrahydrofuran complex, borane-methyl sulfide complex, etc. The corresponding alkyl chlorides are typically prepared from the alcohols with reagents such as hydrogen chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or triphenylphosphine/carbon tetrachloride. For the preparation of alkyl bromides, the alcohol is commonly treated with reagents such as hydrogen bromide, phosphorous tribromide, triphenylphosphine/bromine, or carbonyidiimidazole/allyl bromide (Kamijo, T., Harada, H., Iizuka, K. Chem. Pharm. Bull. 1983, 38, 4189). To access alkyl iodides, one typically reacts the alcohol with reagents such as triphenylphosphine/iodine/imidazole or hydogen iodide. Alkyl chlorides can be converted to the more reactive alkyl bromides or alkyl iodides by treatment with an inorganic salt such as sodium bromide, lithium bromide, sodium iodide, or potassium iodide in solvents such as acetone or methyl ethyl ketone. Alkyl sulfonates can also be used as electrophiles or can be converted to alkyl halides. Sulfonates are prepared from the alcohol using a mild base such as triethylamine or pyridine and a sulfonyl chloride in an inert solvent such a methylene chloride or diethyl ether. Conversion to the halide is accomplished by treatment with an inorganic halide (sodium iodide, sodium bromide, potassium iodide, potassium bromide, lithium chloride, lithium bromide, etc) or a tetrabutylammonium halide. 
Cinnamic acids or esters are commonly available from commercial sources and can by converted to formula 37 or 38 alkylating agents as follows (see SCHEME 23). The cinnamic acid or ester derivatives are reduced by hydrogenation in the presence of palladium or platinum catalysts typically in protic solvents (e.g., methanol or ethanol), tetrahydrofuran, or ethyl acetate. Reduction and conversion to the alkyl halide or sulfonate as described in SCHEME 22 provides formula 38. Where appropriate, the cinnamic acids or esters are converted directly to formula 39 alcohols by treatment with reagents such as lithium aluminum hydride in inert solvents such as tetrahydrofuran and diethyl ether. Alternatively, the cinnamic acid or ester can be reduced to the formula 40 allylic alcohol using reagents such as lithium aluminum hydride/aluminum chloride, diisobutylaluminum hydride, or lithium borohydride. Conversion to the allylic halide or sulfonate as described in SCHEME 22 provides formula 37 reagents. 
The preparation of formula 41 alkylating agents (wherein W and M are as described in the Summary above) are described in SCHEME 24. Formula 42 compounds are alkylated with a variety of bases the choice of which is dependent on the nature of W and M. Some preferred bases are sodium hydroxide, sodium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and potassium tert-butoxide, etc. Treatment of the resulting anion with a variety of dialkylhalides generates the desired formula 41 alkylating agents. For the preparation of compounds where W represents an oxygen and M is an aromatic ring, the preferred conditions involve formation of the alkoxide anion with sodium hydroxide followed by addition of a dihaloalkane, e.g. dibromoalkane. The reaction is normally performed in water at about 75xc2x0 C. to about 125xc2x0 C. 
Aldehydes useful for the chemistry described in SCHEME 5 are available from commercial sources or can be prepared from available intermediates using methods known to those skilled in the art. SCHEME 25 demonstrates an exemplary method used to prepare formula 43 hydroxy aldehydes (where M in SCHEME 5 contains a hydroxy substituted alkyl group). Treatment of a dialdehyde, where one of the aldehydes is protected as a formula 44 acetal (wherein the OR groups are conventional substituents used in an acetal protecting group), with an organometallic reagent (LMetal), preferably an organolithium or Grignard reagent, in an inert solvent such as tetrahydrofuran or diethyl ether, provides formula 45 compounds. Subsequent acetal hydrolysis under mildly acidic conditions, e.g. dilute hydrogen chloride, Amberlyst-15 resin, silica gel, or other reagents as described in xe2x80x9cProtecting Groups in Organic Synthesis,xe2x80x9d Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc., 1991 provides the desired formula 43 hydroxy aldehydes. 
Chloromethyl Intermediates
Intermediate chloromethyl compounds can be prepared as described in SCHEMES 26 and 27. In general, the appropriate formula 101 or 103 sulfonamide or carboxamide is treated with a formaldehyde equivalent such as paraformaldehyde in an inert organic solvent such as methylene chloride or chloroform with a suitable catalyst such as HCl, zinc chloride or trimethylsilyl chloride at temperatures ranging from about 0xc2x0 C. to about 60xc2x0 C. to give the formula 102 and 104 chloromethyl derivatives, respectively. 
Some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Formula I precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
The starting materials and reagents for the above described compounds, are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used therein, are related to, or are derived from compounds found in nature, in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature. Such compounds include, for example, prostaglandins.
Some of the compounds of this invention have asymmetric carbon atoms and therefore are enantiomers or diastereomers. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known Mr s, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
Many of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention are basic and they form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
In addition, when the compounds of this invention form hydrates or solvates they are also within the scope of the invention.
The utility of the compounds of the present invention as medical agents for the reduction of intraocular pressure and accordingly to treat glaucoma is demonstrated by the activity of the compounds of this invention in conventional assays, including the in vivo assay and a receptor binding assay. Such assays also provide a means whereby the activities of the compounds of this invention can be compared to each other and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Intraocular pressure may be measured by pneumatonometry in normal monkeys. Studies are performed in conscious animals trained to accept pnbeumatonometry. The compound to be tested is administered topically to one eye in a 25 xcexcl volume drop, the contralateral eye receives vehicle as a control. Statistical analysis is by Student""s paired t test.
Membrane Preparation: All operations are performed at 4xc2x0 C. Transfected cells expressing prostaglandin E2 type 1 receptors (EP1), type 2 (EP2), type 3 (EP3) or type 4 (EP4) receptors are harvested and suspended to 2 million cells per ml in Buffer A [50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA, 1 mM Pefabloc peptide, (Sigma, St. Louis, Mo.), 10 uM Phosporamidon peptide, (Sigma, St. Louis, Mo.), 1 uM Pepstatin A peptide, (Sigma, St. Louis, Mo.), 10 uM Elastatinal peptide, (Sigma, St. Louis, Mo.), 100 uM Antipain peptide, (Sigma, St. Louis, Mo.)]. These are lysed by sonification with a Branson Sonifier (Model #250, Branson Ultrasonics Corporation, Danbury, Conn.) in 2 fifteen second bursts. Unlysed cells and debris are removed by centrifugation at 100xc3x97g for 10 min. Membranes are then harvested by centrifugation at 45,000xc3x97g for 30 minutes. Pelleted membranes are resuspended to 3-10 mg protein per ml, protein concentration being determined according to the method of Bradford [Bradford, M., Anal. Biochem., 72, 248 (1976)]. Resuspended membranes are then stored frozen at xe2x88x9280xc2x0 C. until use.
Binding Assay: Frozen membranes prepared as above are thawed and diluted to 1 mg protein per ml in Buffer A. One volume of membrane preparation is combined with 0.05 volume test compound or buffer and one volume of 3 nM 3H-prostaglandin E2 (#TRK 431, Amersham, Arlington Heights, Ill.) in Buffer A. The mixture (205 xcexcL total volume) is incubated for 1 hour at 25xc2x0 C. The membranes are then recovered by filtration through type GF/C glass fiber filters (#1 205401, Wallac, Gaithersburg, Md.) using a Tomtec harvester (Model Mach II/96, Tomtec, Orange, Conn.). The membranes with bound 3H-prostaglandin E2 are trapped by the filter, the buffer and unbound 3H-prostaglandin E2 pass through the filter into waste. Each sample is then washed 3 times with 3 ml of [50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM EDTA]. The filters are then dried by heating in a microwave oven. To determine the amount of 3H-prostaglandin bound to the membranes, the dried filters are placed into plastic bags with scintillation fluid and counted in a LKB 1205 Betaplate reader (Wallac, Gaithersburg, Md.). IC50s are determined from the concentration of test compound required to displace 50% of the specifically bound 3H-prostaglandin E2.
Administration of the compounds of this invention can be via any method which delivers a compound of this invention systemically and/or locally (e.g., topically). These methods include oral routes, parenteral, intraduodenal routes, etc.
The amount and timing of compounds administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgement of the prescribing physician. Thus, because of patient to patient variability, the dosages given below are a guideline and the physician may titrate doses of the drug to achieve the treatment (e.g., reduction of intraocular pressure) that the physician considers appropriate for the patient.
In general an effective dosage for the compounds of this invention described above is in the range of 0.001 to 100 mg/kg/day, preferably 0.01 to 50 mg/kg/day.
The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle or diluent. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form.
For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
For purposes of transdermal (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
For topical ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other wuitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In any event, the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat reduce intraocular pressure.
The compounds of this invention either alone or in combination with each other or other compounds generally will be administered in a convenient formulation. The following formulation examples only are illustrative and are not intended to limit the scope of the present invention.
In the formulations which follow, xe2x80x9cactive ingredientxe2x80x9d means a compound of this invention.
Formulation 1: Gelatin Capsules
Hard gelatin capsules are prepared using the following:
A tabelt formulation is parepared using the ingredients below:
Formulation 2: Tablets
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows:
Formulation 3: Tablets
The active ingredients, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0-60xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows:
Formulation 4: Suspensions
The active ingredient are passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. An aerosol solution is prepared containing the following ingredients:
Formulation 5: Aerosol
The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30xc2x0 C., and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container. Suppositories are prepared as follows:
Formulation 6: Suppositories
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
An intravenous formulation is prepared as follows:
Formulation 7: Intravenous Solution
The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute.
The active ingredient above may also be a combination of agents.
NMR spectra were recorded on a Varian XL-300 (Varian Co., Palo Alto, Calif.) a Bruker AM-300 spectrometer at about 23xc2x0 C. at 300 MHz for proton and 75.4 mHz for carbon (Bruker Co., Billerica, Mass.) or a Varian Unity 400 at 400 Mhz for proton nuclei. Chemical shifts are expressed in parts per million downfield from trimethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet, q, quartet; m, multiplet; bs=broad singlet. Resonances designated as exchangeable did not appear in a separate NMR experiment where the sample was shaken with several drops of D2O in the same solvent. Atmospheric pressure chemical ionization (APCI) mass spectra were obtained on a Fisons Platform II Spectrometer. Chemical ionization mass spectra were obtained on a Hewlett-Packard 5989 instrument (Hewlett-Packard Co., Palo Alto, Calif.) (ammonia ionization, PBMS). Where the intensity of chlorine or bromine-containing ions are described the expected intensity ratio was observed (approximately 3:1 for 35Cl/37Cl-containing ions) and 1:1 for 79Br/81Br-containing ions) and the intensity of only the lower mass ion is given.
Column chromatography was performed with either Baker Silica Gel (40 xcexcm) (J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences, Gibbstown, N.J.) in glass columns under low nitrogen pressure. Radial Chromatography was performed using a Chromatron (model 7924T, Harrison Research) Unless otherwise specified, reagents were used as obtained from commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran, and dichloromethane used as reaction solvents were the anhydrous grade supplied by Aldrich Chemical Company (Milwaukee, Wis.). Microanalyses were performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y. The terms xe2x80x9cconcentratedxe2x80x9d and xe2x80x9ccoevaporatedxe2x80x9d refer to removal of solvent at water aspirator pressure on a rotary evaporator with a bath temperature of less than 45xc2x0 C. Reactions conducted at xe2x80x9c0-20xc2x0 C.xe2x80x9d or xe2x80x9c0-25xc2x0 C.xe2x80x9d were conducted with initial cooling of the vessel in an insulated ice bath which was allowed to warm to room temperature over several hours. The abbreviation xe2x80x9cminxe2x80x9d and xe2x80x9chxe2x80x9d stand for xe2x80x9cminutesxe2x80x9d and xe2x80x9choursxe2x80x9d respectively.